Spongistatin

The multicomponent linchpin coupling of silyl dithianes with epoxides was very efficiently used to access both the AB and CD spiroketal fragments of spongistatin. 

Scheme 8.32 Second-generation construction of the AB spiroketal system of spongistatin.

Scheme 8.43 Evanss approach for the (S-stereoselective introduction of the C44-C51 side chain of spongistatin 2.

Evans developed a new method for the synthesis of [(-C-allylglycosides, based on BusSnOTf-mediated ring-opening of glycal epoxides with allylstannanes as nucleophiles [81a], This methodology has been efficiently used in the (3-stereoselective introduction of the side chain (C44-C51) of spongistatin 2 (Scheme 8.43) [81b,c]. 

For further use of dithiane chemistry in the synthesis of spongistatin, see also a)... 

This methodology was also used in the connecting of two major fragments in the synthesis of spongistatins.252... 

Cycloadducts have also been used as starting materials for the synthesis of the C29-C37 segment of a spongistatin <99TA1539> and the synthesis of the cyathin core <990L1535>. 

TOTAL SYNTHESIS OF SPONGISTATIN 1 (ALTOHYRTIN A) A TALE OF TEN ALDOLS... 

This chapter attempts to recount some of the highs and lows encountered during the Paterson group s total synthesis of spongistatin 1/altohyrtin A, an extremely rare marine macrolide with a seductively complex structure in combination with displaying promising anticancer properties. We provide the reader with an emotional roller coaster ride through a project that spanned some 7 years, with early studies aimed at... 

Figure l. Originally proposed structures for spongistatin 1 (1), altohyrtin A... 

The C1-C15 fragment of spongistatin 1, comprising the AB-spiroacetal 4,10 exhibits an axial-axial disposition of the two acetal oxygen atoms at C7 and hence benefits from two stabilising anomeric effects (Figure 3). Based on this, it was expected that the correct spiroacetal would be... 

Hie Ci -C28 fragment of spongistatin 1, comprising the CD-spiroacetal 5, exhibits an axial equatorial disposition of the two acetal oxygen atoms and hence, unlike the A B-spiroacctal system, benefits from only one stabilising anomcric effect (Figure 4). 

At the outset of our work on this section of the spongistatin structure.15 it was not known whether an internal acetalisation procedure, analogous to that employed for the AR subunit, would lead to the desired spiroacctal 22a rather than the potentially more stable 22b. However, the axial Cm hydroxyl may hydrogen bond to an acetal oxygen, providing structure 22a additional stability not available to 22b, and this might be exploited in our synthetic endeavours. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The CD-spiroacetal subunit of the spongistatins proved to be of an appropriate level of complexity that several different synthetic strategies were evaluated. Access to the desired spiroacetal 5 was readily achieved by acid catalysed equilibration of the mixture of spiroacetals in aprotic solvents, followed by separation and recycling of the undesired isomer. Furthermore, the 1,5-anti aldol reaction of methyl ketones proved invaluable for construction of certain portions of the target molecule. 

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